Human Immunodeficiency Virus (HIV) continues to pose a significant challenge to global health. There are no available vaccines and despite some improvement in treatment options, there continues to be an unmet medical need for new HIV treatments for front-line and salvage therapy. The burden of HIV infection continues to insistently grow in Africa and in specialized populations in the West (homosexual and drug abuser populations). HIV management requires life-long treatment resulting in drug resistance in existing therapies as well as tolerability concerns with some classes of treatments. Combination therapy has emerged as the best treatment strategy to manage chronic viral infections reinforcing the need for continued development of novel HIV antiviral agents with novel mechanisms of action that can become part of cross-class combination regimens. Current cocktails are comprised of Protease Inhibitor, Nucleoside and Non-nucleoside analogs which have been in circulation for years, leading to multi-drug resistance reinforcing the need for second generation combination regimens that rely on novel mechanisms of action. Novira is developing a new class of antiviral therapeutics which target and misdirect HIV capsid assembly. Recent work done by ourselves and other research groups underscores HIV capsid assembly as a pharmacologically validated, yet an underexploited drug target for the development of potent HIV inhibitors. Capsids are highly conserved viral proteins and thus promise a higher genetic barrier to resistance if drugs targeting capsids were to be developed. Novira's "capsid assembly effector" antivirals have the potential to become first-in-class HIV therapeutics that deliver superior efficacy and tolerability as part of combination therapy with existing drugs and thereby delivering a transformational therapeutic option to patients with chronic HIV infection. Novira has conducted a high-throughput screen of pre-evaluated and especially selected screening library possessing features of drug-like molecules that have known structural features suited to capsid type drug targets that utilize protein-protein interactions. This privileged screening library has yielded high quality, drug- like Hits against HIV capsid assembly in a functional assembly assay. Phase I of this proposal aims to fund Hit- to-Lead activities and nominate Lead molecules for Optimization in Phase II for pre-clinical development. We will develop a Structure-activity-relationship (SAR) and build a pharmacophore map highlighting chemical features of the molecules responsible for biological activity against capsid assembly. This will be done by testing close analogs of current high-ranking hits that we are currently generating through parallel library synthesis. As part of this proposal, these analogs will be tested in vitro in functional, cell-free assembly assays to confirm biochemical activity followed by testing in cell-based antiviral assays to confirm biological activity. Detailed mechanism of action studies proposed here will enable us to select the best 1-3 drug-like Lead molecules that target HIV capsid assembly. Mechanism of action studies will encompass NMR studies of the inhibitors with the HIV Capsid in complex to confirm binding sites of select inhibitors as well as resistance selection of these compounds to confirm that mutations in resistant viruses selected through serial passage, map to the capsid protein sites of assembly. At the end of this proposal we will nominate 1-3 mechanistically characterized, drug-like Lead molecules that possess a robust SAR, target HIV assembly and are ready for Optimization through Medicinal Chemistry for eventual Preclinical studies. PUBLIC HEALTH RELEVANCE: Human Immunodeficiency Virus (HIV) is a significant burden on global health. Due to resistance and side-effects of existing treatment regimens, new drugs with novel mechanisms of action are needed. Phase I of this project will deliver a new class of Lead molecules against HIV that target capsid assembly. Molecules that target HIV Capsid assembly offer a unique promise of providing high genetic barrier to resistance as well as complement existing therapies as part of combination therapy.